Geoffrey West, Santa Fe Institute

Physics Talk Background Papers:

A quantitative theory of solid tumor growth and vascularization

Supplimental Material

Don Ingber, Harvard

Central Question & Paper:

• What properties of the embryonic micromenviroment convey its ability to induce cancer differentiation?

Robert Getzenberg (JHU) & Don Coffey (JHU) : Additional Material

These three articles will flow towards the metastatic aspects of the concepts in our discussions. 

 

We understand that Dr. Michor is attending the meeting but wanted to include one of the papers on which she is an author since it raises what we feel is a very important concept.  This manuscript on quasispecies connects chromosome structure to evolution and cancer and introduces some mathematical issues.  The recent paper on pattern recognition will provide a link to the physics on this topic. We are sure that Herb Levine will apply his vast experience to this problem.  The last of the papers is an old review on the tissue matrix that sets the background for the structural aspects of what we will discuss. 

Background Papers:

• Reaction-Diffusion Model as a Framework for Understanding Biological Pattern Formation
• Genetic instability and the quasispecies model
• The Tissue Matrix: Cell Dynamics and Hormone Action

Chuck Drake, Johns Hopkins University

Three Problems:

• Do cancer cells metastasize as single cells, as clusters of tumor cells, as clusters of tumor and myeloid cells, or as fusions between tumor cells and macrophages?
• What is the relative role of passive (fluid dynamic) versus active processes (diapedesis, extravascation) in the establishment of metastases from tumor cells circulating in the vascular or lymphatic compartments?
• At what stage in the metastatic process are tumor cells most susceptible to immunological intervention? 

Background Papers:

• Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed?
• Integrins in cancer: biological implications and therapeutic opportunities
• Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis
• Circulating Tumor Cell Clusters in the Peripheral Blood of Colorectal Cancer Patients

Robert Vessella, University of Washington

Key Challenge:

• Development of the technologies that will allow us to isolate viable single metastatic cells and then interrogate those individual cells for molecular signatures and biological behavior.   This remains a huge challenge especially in the study of dormancy.

Background Papers:

• Extracellular matrix: A gatekeeper in the transition from dormancy to metastatic growth 
• Tumor Dormancy and Metastasis

Scott Guelcher, Vanderbilt

Three Questions:

• What characteristics unique to the bone microenvironment induce tumor cells to express osteolytic factors after the tumor becomes established in bone?
• Over what range of tissue-level mechanical properties can tumor cells respond to the rigidity of the microenvironment?
• Are tumor cells genetically programmed to metastasize to bone or are they attracted to the unique characteristics of the bone microenvironment?

Background Papers:

• Inhibition of Rho-Associated Kinase Signaling Prevents Breast Cancer Metastasis to Human Bone
• Matrix Rigidity Induces Osteolytic Gene Expression of Metastatic Breast Cancer Cells
• Extracellular Matrix Rigidity Promotes Invadopodia Activity

Chris Contag, Stanford

Three Problems:

• The small numbers of cells that comprise early metastatic sites make these sites difficult to locate.
• The nature of metastatic cells is uncertain without clear cell surface markers or other known distinguishing characteristics, and therefore identifying those cells is difficult. Using cell surface markers that are characteristic of late stage disease may not be relevant.
• The characteristics of a cancer cell the enable it to escape the primary site are not well understood and the markers on such cells have not been described.

Background Papers:

• Synergistic Antitumor Effects of Immune Cell-Viral Biotherapy

• Integrating the biological characteristics of oncolytic viruses and immune cells can optimize therapeutic benefits of cell-based delivery

• Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models.

Lalit Patel, University of Michigan

The progression of prostate cancer is believed to occur in sequential steps. A primary tumor forms, becomes aggressive, disseminates aggressive cells that invade a secondary site, forms a metastasis, the metastases metastasize, and a lethal phenotype emerges. Empirical findings challenge this linear view of disease progression. It has been demonstrated that prostate cancer disseminates to and invades the bone marrow of patients who present with organ-confined early stage primary disease. Although these cells (DTCs) are present at prostatectomy - biochemical evidence of disseminated disease does not present for several years and the cells themselves lack proliferation markers. These findings suggest a latent-phase in which the majority of Homo sapien bone disseminated prostate cancer cells lack metastatic potential. This raises the following questions:

1) Metastogenesis by DTCs:

• Are bone metastases in Homo sapiens the slow expansion of rare non-dormant clones or is there a time delayed recurrent secondary-site specific "metastogenic-transformation" that activates skeletal tumor formation by DTCs?

2) Heterogeneity of DTCs:

• how many molecular-phenotypes of dormancy are there amongst Homo sapien prostate cancer DTCs?
• how many dormancy escape mechanisms are there?
• are dormancy escape mechanisms redundant, convergent, or divergent?
• is the escape route from dormancy ultimately taken by DTCs predestined by clonal origins or selected for by recurrent secondary transformations at the metastatic site?

3) Seed-Soil relationship of DTC dormancy and the bone microenvironment:

• is dormancy a byproduct of selection for dormant clones by the metastatic process?
• is dormancy induced by the bone marrow microenvironment/metastatic niche?
• what microenvironmental cues (molecular, structural, or mechanical) would confer/ablate tumor cell dormancy?
• can dormant DTCs “prime-the-soil” through microenvironmental manipulation for future tumor formation?

Suggested Readings:

• Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009 Apr;9(4):302-12.
• Holcomb IN, Grove DI, Kinnunen M, Friedman CL, Gallaher IS, Morgan TM, Sather CL, Delrow JJ, Nelson PS, Lange PH, Ellis WJ, True LD, Young JM, Hsu L, Trask BJ, Vessella RL. Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate cancer patients. Cancer Res. 2008 Jul 15;68(14):5599-608.
• Psaila B, Kaplan RN, Port ER, Lyden D. Priming the 'soil' for breast cancer metastasis: the pre-metastatic niche. Breast Dis. 2006-2007;26:65-74.

Evan Keller, University of Michigan

Three Problems:

• Why is prostate cancer osteoblastic (i.e. most cancers when they spread to bone result in bone resorption (i.e., osteolytic); whereas, prostate cancer results in bone production (i.e. osteoblastic).
• Why does prostate cancer preferentially metastasize to bone as opposed to other sites.
• How can we successfully treat metastases that are highly heterogenous (i.e  within one patient, different metastases have different properties).

Background Papers:

• Histopathological Assessment of Prostate Cancer Bone Osteoblastic Metastases
• OSTEOBLASTS IN PROSTATE CANCER METASTASIS TO BONE

Robert Getzenberg, Johns Hopkins University

Three Questions:

• Metastatic cancer cells have amplified evolutionary capabilities that allow them to develop resistance to therapeutic approaches.  This may be enhanced by niches/microenvironments being emptied by “sensitive” populations that do not survive.  What role do physical and/or structural properties play in the development of resistance and how can modification of these by used to hinder the evolution of cancer?
• The concept that cancer cells metastasize as single cells may not be correct.  Groups of cancers cells along with what appear to be perhaps supporting players have been identified.  Do cells, other than the tumor cells themselves, “travel” with the cancer cell and aid in the development of metastatic sites?  If so, are they from the site of origin or are they recruited from other sources?  Can we image these?
• It appears that heat can be used to increase the sensitivity cancer cells to other forms of therapy and that the price that the cancer cells pays for being so able to develop resistance to therapy is a sensitivity to microenvironmental stresses.  What physical properties of the cells have been altered that creates this sensitivity to stresses?  

Don Coffey, Johns Hopkins University

Central Question:

Why is there so much variation (heterogeneity) within solid tumors in relation to  cell structure and function and how might this relate to energy, information transfer, and self-organization?

Gary Stein, University of Massachusetts

Three Problems:

• Epigenetic control in tumorigenesis, tumor progression and metastasis ¹
• Nuclear microenvironments in biological control and cancer ²
• Cell adhesion and motility in tumor progression ³

References:

¹Zaidi SK, Young DW, Montecino M, Lian JB, van Wijnen AJ, Stein JL, Stein GS. (2010) Mitotic bookmarking of genes: a novel dimension to epigenetic control. Nature Reviews Genetics Aug;11(8):583-9. Epub 2010 Jul 13.

²Zaidi SK, Young DW, Javed A, Pratap J, Montecino M, van Wijnen AJ, Lian JB, Stein JL, Stein GS   (2007) Nuclear microenvironments in biological control and cancer.  Nature Reviews Cancer, 7:454-463.

³Altieri DC, Languino LR, Lian JB, Stein JL, Leav I, van Wijnen AJ, Jiang Z, Stein GS. Article.  (2009) Prostate cancer regulatory networks. J Cell Biochem. Aug 1;107(5):845-52.

Lance Munn, Harvard

Three Questions:

• Can we identify patients who would benefit from treatment aimed at preventing metastasis or further metastasis? 
• How does the accumulation of compressive stress affect invasion and metastasis?
• What role do host stromal cells or cancer cell cooperation play in invasion and metastasis?

 

Background Papers:

• Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis
• Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed?
• Mechanisms of collective cell migration at a glance

Yibin Kang, Princeton

Questions

• Do tumor cells behave differently as solitary cells (disseminated tumor cells or micrometastasis) and as overt metastasis.  Is a critical mass required for tumor cells to manifest their full malignant potential and how does this relates to metastatic dormancy?
• Is there a fitness cost for tumor cells to overcome different hurdles of metastasis?  For example, when tumor cells undergo epithelial mesenchymal transition to invade and migrate, are they more susceptible to certain drugs. 
• What are the key molecular pathways that mediate tumor-stromal interactions in metastasis?  How to we effectively deliver therapeutics to disseminated tumor cells or micrometastasis to prevent distant recurrence?

Background Papers

• ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis
• A multigenic program mediating breast cancer metastasis to bone
• Imaging transforming growth factor-b signaling dynamics and therapeutic response in breast cancer bone metastasis

Ken Pienta, University of Michigan

Three questions:

• How efficient is the metastatic process? What are the qualities of a cancer cell that is a successful metastatic seed?
• How do the physical qualities of the target organ affect the establishment of a metastasis?
• How do cells survive the turbulence of the circulation?

Background Papers:

• The Lethal Phenotype of Cancer: The Molecular Basis of Death Due to Malignancy
• Pathogenesis and Treatment of Prostate Cancer Bone Metastases: Targeting the Lethal Phenotype

Meeting Logistics

Dates:
November 1-2, 2010 (October 31st, registration and opening discussion with refreshments in the evening for those available, time 6-8pm.)


Location:
Hilton-Arlington, 950 North Stafford Street, Arlington, VA 22203
Note: Reservations and hotel payment will be made via meeting coordinator.  Please forward your reservation dates to Sara. 

Directions & Transportation: Link

Travel:
Please make your own travel arrangements.  Attendee's are encouraged to make air/ground transportation reservations as early as possible to capitalize on reduced fares. Currently, the organizers are budgeted for air travel at the following RT rates: West coast ~$700; Mid-West, ~$600; and East Coast, ~$300. Air/ground transportation will be reimbursed after the meeting by UCSD. You will be given detailed instructions on how to submit your travel reimbursements at or shortly after the meeting.

Please be aware of the following restrictions: UC will reimburse you for economy/coach class air travel (or the equivalent of an economy/coach fare if you decide to fly business/first class) and original receipts are required. For those living within driving distance,  you may receive a mileage per diem (and parking fee reimbursement) if you use your personal vehicle. Taxis, shuttles and train expenses (within reasonable limits) will also be reimbursed.

Please forward your itinerary and ticket price to the meeting coordinator, Sara Bradley at sara.bradley@comcast.net.

Agenda:
Sunday, October 31st: registration and opening discussion with refreshments in the evening for those available, time 6-8pm.
Monday, November 1: talks and discussion will run the full day on Monday, dinner to follow.
Tuesday, November 2: talks and discussion will run to approximately 3pm.
Detailed agenda tba.


Meeting Coordinator:
Sara Bradley

Physics of Cancer Metastasis

Physics of Cancer Metastasis